(Philadelphia, PA) – In a preclinical efficacy trial, the cancer
drug paclitaxel (Paxceed) – which exerts its effects by binding
to and stabilizing microtubules inside cells – reduced the adverse
effects of Alzheimer’s disease (AD)-like pathology in a mouse model.
Researchers from the University of Pennsylvania School of Medicine
showed that the microtubule-stabilizing drug Paxceed helps correct the
problems caused by clumped tau proteins in the nerve cells of mice. “Our
hope is that microtubule-stabilizing drugs could be used to treat Alzheimer’s
and other related diseases,” says John Q. Trojanowski, MD,
PhD, Director of the Institute on Aging and Co-director of the
Center for Neurodegenerative Disease Research and the Marian S. Ware Alzheimer
Program at Penn. This research appears in the December 20 early online
edition of the Proceedings of the National Academy of Sciences.

Tau amyloids are misshapened, insoluble proteins that clump in the brain
and elsewhere and cause a host of debilitating diseases. Since many neurodegenerative
diseases share or contribute to this pathology, the focus of therapy has
been on drugs that break up these aggregates. Virginia M.-Y. Lee,
PhD, Director of the Center for Neurodegenerative Disease Research,
and Trojanowski introduced the concept of using microtubule-stabilizing
drugs over a decade ago, and this is the first study to confirm their
potential as a new class of drug for neurodegenerative disorders. “Now
everyone is focused on drugs that disrupt the aggregated protein,”
says Trojanowski. “We’re working on that too, but we also
wanted to find a drug that replaces the clumped tau in sick neurons.”

Microtubule-binding drugs derived from plants (taxol) and other biological
organisms such as sponges (discodermolides) have been used as anti-cancer
drugs because they prevent cells from dividing. They do this by keeping
microtubules stabilized, which blocks cell division and causes cell death.
Microtubules are protein structures found within cells.

Since neurons do not divide, Paxceed does not affect them in the same
way as normally dividing cells and tumor cells. Instead, microtubule-binding
drugs have other effects in nerve cells similar to the function of the
protein tau.

Tau
binds microtubules, the highway system of axons in nerve cells. Mutations
in the tau gene cause neurons to lose their ability to send and
carry signals over time. (Click on thumbnail to view full-size image).
“These are proteins that we all have in our brains and, as long
as they stay soluble and properly folded, there’s no disease,”
says Trojanowski. “When these misfolded proteins aggregate and form
sheets called fibrils that accumulate in different parts of the brain,
that’s when things go awry.” This happens when the cell’s
garbage disposal–the proteosome–isn't working properly or
is overwhelmed, causing such affects as cell death, oxidative stress,
and in this case impaired axonal transport, which is linked to many neurodegenerative
diseases. Impaired axonal transport of proteins and other cargoes needed
to maintain synapses can cause nerve cell loss with subsequent dementia,
parkinsonism or weakened motor skills in peripheral muscles, and later
muscle atrophy.

The protein tau, like Paxceed (or other natural products such as taxanes
and discodermolides), is required to stabilize the microtubule. “Think
of tau as the cross-tie of the microtubule train track,” says Trojanowski.
“The tracks will handle the traffic as long as they are parallel
and there are substrates for transport. If the cross-ties are missing,
the tracks will wobble and the train will run off the tracks.”

In a sick neuron, tau is clumped into aggregates, so the microtubule cross-ties
are missing, the tracks break, and transmission of nerve signals fails.
In the hopes of restoring the microtubule tracks to their original supportive
structure, the researchers gave mice Paxceed to replace the now unavailable
tau. The team, led by Bin Zhang, PhD, a Senior Research
Investigator in Trojanowski’s and Lee’s laboratory, gave the
tau transgenic mice weekly injections of Paxceed at a high and low dose
for 12 weeks. At both doses, more protein traveled down the spinal axon
and the density of microtubules was greater in the Paxceed-treated mice.
The drugs also reduced motor impairment in the tau transgenic mice.

Because microtubule-binding drugs such as Paxceed are approved for treating
patients with cancer and a limited number of other diseases, it might
be possible to move quickly to clinical trials of these types of compounds,
say the researchers. However, it will be necessary to find microtubule-binding
drugs that can cross the blood-brain barrier, where they can exert their
beneficial effects on nerve cells inside the brain.

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